Development of Drug Delivery Technology for Stem Cell Based TMJ Regeneration

基于干细胞的颞下颌关节再生药物输送技术的发展

基本信息

批准号：
10010173
负责人：
Mo Chen
金额：
$ 75.2万
依托单位：
WNT SCIENTIFIC, LLC
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10010173
关键词：
American Animal Model Anti-Inflammatory Agents Biological Biology Cartilage Cells Chondrocytes Collaborations Communication Complex Connective Tissue Data Degenerative polyarthritis Dental Occlusion Disease Drug Delivery Systems Encapsulated Extracellular Matrix FDA approved Failure Family suidae Fibrocartilages Fostering Goals Growth Factor Health Human Hyaluronic Acid Hydrogels Injectable Intra-Articular Injections Joints Knee Osteoarthritis Laboratories Legal patent Life Ligaments Link Lubrication Mastication Mediating Modeling Molecular Weight Mus Muscle National Institute of Dental and Craniofacial Research Natural regeneration Nature Operative Surgical Procedures Oryctolagus cuniculus Pain management Pathology Patients Peer Review Pharmaceutical Preparations Pharmacology Phase Play Proteoglycan Quality of life Recombinants Recreation Regenerative Medicine Replacement Arthroplasty Respiration Signal Transduction Small Business Technology Transfer Research Speech Structure Synovial Fluid Synovial joint System Technology Transfer Temporomandibular Joint Temporomandibular Joint Disorders Temporomandibular joint osteoarthritis Testing Therapeutic Time Tissues Transplantation Universities WNT Signaling Pathway base cartilage repair cost drug development inhibitor/antagonist injured innovation joint injury lubricin minimally invasive novel pre-clinical regenerative regenerative therapy repaired research and development stem cell technology stem cell therapy stem cells tissue regeneration treatment strategy

项目摘要

1 ABSTRACT 2 The temporomandibular joint (TMJ) is a complex joint system critical for dental occlusion, mastication, 3 respiration and speech. The TMJ is comprised of a network of muscles, ligaments, and a 4 fibrocartilaginous disc and condyle. Temporomandibular disorders (TMDs) afflict over 10 million 5 Americans at an annual cost of ~$4 billion, per the NIDCR. Degenerative types of TMDs, including 6 TMJ osteoarthritis (OA), are debilitating, compromise quality of life, and causes permanent tissue 7 loss. Current TMJ OA treatments are typically two-fold, involving either pain management or invasive 8 surgeries, such as total joint replacements with high failure rates. There is a paucity of minimally 9 invasive TMJ therapies that promote tissue regeneration. 10 Regenerative medicine promises the recreation functional tissue that is loss from disease. Thus 11 exploiting the regenerative capabilities of resident stem cells to repair TMJ may represent a minimally 12 invasive stem cell-based treatment for TMJ OA. We have identified fibrocartilage stem cells 13 (FCSCs) that reside in the TMJ condyle superficial zone. Transplanted FCSCs self-organize and 14 regenerate cartilage. Wnt/Catenin signaling promotes proliferation and inhibits chondrogenic 15 differentiation of FCSCs. However, over-active Wnt/Catenin deplete FCSCs and cause TMJ OA 16 in mice, rabbits and humans. These data suggest that inhibiting Wnt/Catenin in FCSCs may serve 17 as a stem cell-based therapeutic strategy for the treatment of TMJ OA. In fact, we showed that 18 blocking Wnt via weekly TMJ intra-articular injections of the Wnt inhibitor sclerostin ameliorated TMJ 19 OA in a rabbit TMJ injury model. However, a pharmacological drug delivery system for chairside, 20 sustained release sclerostin administration to human TMJ OA patients has not been defined. 21 Based on our preliminary data, we hypothesize that delivery of an injectable, sustained release 22 hyaluronic acid-sclerostin hydrogel will target resident TMJ fibrocartilage stem cells to regenerate 23 TMJ.

1 摘要 2 颞下颌关节 (TMJ) 是一个复杂的关节系统，对于牙齿咬合、咀嚼、 3 呼吸和言语颞下颌关节由肌肉、韧带和神经网络组成。 4 纤维软骨盘和髁突疾病 (TMD) 困扰着超过 1000 万人。根据 NIDCR，5 个美国人每年花费约 40 亿美元，其中包括退化类型的 TMD。 6 颞下颌关节骨关节炎 (OA) 会使人衰弱，影响生活质量，并导致永久性组织损伤 7 目前的 TMJ OA 治疗通常有两个方面，要么是疼痛管理，要么是侵入性治疗。 8 次手术，如全关节置换术，失败率较高。 9 种促进组织再生的侵入性 TMJ 疗法。 10 再生医学有望恢复因疾病而丧失的功能组织。 11 利用驻留干细胞的再生能力来修复 TMJ 可能代表了最低限度的 12 基于侵入性干细胞的 TMJ OA 治疗方法我们已经鉴定出纤维软骨干细胞。 13 (FCSC) 位于 TMJ 髁浅表区，移植的 FCSC 会自我组织和形成。 14 再生软骨。Wnt/连环蛋白信号促进增殖并抑制软骨形成。 15 FCSC 的分化然而，过度活跃的 Wnt/连环蛋白会消耗 FCSC 并导致 TMJ OA。 16 在小鼠、兔子和人类中这些数据表明抑制 FCSC 中的 Wnt/连环蛋白可能起作用。 17 作为治疗 TMJ OA 的干细胞治疗策略事实上，我们证明了这一点。 18 通过每周 TMJ 关节内注射 Wnt 抑制剂硬化素来阻断 Wnt，改善 TMJ 19 兔 TMJ 损伤模型中的 OA 然而，用于椅旁的药理给药系统， 20 尚未明确对人类 TMJ OA 患者进行持续释放硬化素给药。 21 根据我们的初步数据，我们勇敢地交付了可注射的缓释药物 22 透明质酸-硬化素水凝胶将靶向驻留的 TMJ 纤维软骨干细胞进行再生 23 颞下颌关节。